1. Field of the Invention
The present invention relates generally to the fields of molecular biology, oncology and cardiology. More particularly, it concerns the development of monoclonal antibodies to LRP5/6 and for their use in the treatment of cardiovascular disease and cancer.
2. Background of the Invention
Myocardial infarction (MI) is a leading cause of disability and death. Each year, ˜900,000 Americans experience a MI (American Heart Association, 2003; Topol, 2003). The management of patients with a healing MI includes revascularization during the first hours following infarction. The infarct injury affects the heart globally and induces a process termed “ventricular remodeling” that affects size, shape and function of the heart; this process is strongly linked with progression to heart failure and, ultimately, to morbidity and mortality. In fact, post-infarct remodeling, rather than hypertension and valvular disease, is currently considered to be the most common cause of heart failure (HF) (Id.).
The wound healing observed after MI parallels that seen in other tissues (Holmes et al., 2005; Buja and Entman, 1998; Cleutjens et al., 1999). The first phase is characterized by myocyte death (Holmes et al., 2005; Buja and Entman, 1998; Cleutjens et al., 1999). This process evokes an inflammatory response with disruption of the collagen network and deposition of granulation tissue (Tyagi et al., 1996). The altered post-infarct hemodynamics, in combination with its associated chemokine milieu, result in molecular changes in cardiomyocytes, fibroblasts and endothelial cells that lead to unfavorable remodeling through poorly-defined mechanisms.
After injury, myocyte numbers decrease (American Heart Association, 2003; Topol, 2003). It is well established that there is a direct correlation between the irreversible loss of cardiomyocytes and progression of cardiac dysfunction, adverse remodeling and eventual failure (American Heart Association, 2003; Topol, 2003; Cleutjens et al., 1999). Current therapies have reduced early mortality following MI but fail to address the primary cause of impaired function, the loss of myocytes (Topol, 2003; Sharpe, 2004; Sutton and Sharpe, 2000). Two strategies are being intensely investigated: stem cell transplantation and induction of myocyte proliferation.
Cardiomyocytes exit the cell cycle shortly after birth, and the adult mammalian heart is considered incapable of regeneration after injury (van Amerongen and Engel, 2008). In non-mammalian models (i.e. zebrafish) studies have demonstrated that lost myocardial tissue can be replenished by dedifferentiation and proliferation of differentiated cardiomyocytes (Kikuchi et al., 2010; Jopling et al., 2010). There are several lines of evidence that support the hypothesis that induction of cardiomyocyte proliferation can also promote mammalian heart regeneration. Analysis of human heart failure autopsy tissues indicate that individuals with early mortality have increased percentage of apoptotic myocytes and decreased expression of proliferation markers (Ki-67) compared to longer survivors (Swynghedauw, 1999). Forced cardiac expression of positive regulators of cell cycle progression (i.e. Cyclin A2 or Cyclin D2) in transgenic mice demonstrate enhanced cardiac function and improved remodeling following ischemic injury (van Amerongen and Engel, 2008; Chaudhry et al., 2004). Periostin and FGF1/p38 inhibitors promote myocyte proliferation and also improve cardiac repair (Engel et al., 2006; Kuhn et al., 2007). In summary, augmenting cardiomyocyte number by stimulating cardiomyocyte cell division may help cardiac regeneration following injury.
In spite of these promising reports, it is unlikely that inducing myocyte proliferation alone is sufficient to promote cardiac repair. For example, p38 inhibition (in the absence of FGF) was found to be insufficient to promote repair despite inducing myocyte proliferation (Engel et al., 2006). In addition, c-Myc-induced cardiomyocyte proliferation did not result in improved cardiac function (van Amerongen and Engel, 2008). Thus, other cellular effects and/or modulation of tissue stroma and vasculature may also be important. Finally, none of these extrinsic agents (i.e. periostin, FGF/p38 inhibitors) have been translated into feasible and effective therapies to repair the injured heart. Therefore, new and improved therapeutics for to promote cardiac repair and impede pathogenic cardiac remodeling are needed.